Ekbom, Anders

Brandt, Lena

Askling, Johan

Abstract [en]

Objective. ANCA has come to play an important role in diagnosing vasculitis. In selected populations c-ANCA/PR3-ANCA has a high specificity and sensitivity for vasculitis. In clinical practice, how individuals with c-ANCA/PR3-ANCA but without sufficient evidence of systemic vasculitis should be managed is unclear. We therefore retrospectively assessed the disease panorama and outcome in a consecutive series of individuals with c-ANCA/PR3-ANCA, and studied in detail those individuals who turned out not to fulfil criteria for vasculitic disease.

Methods. The study population consisted of 74 consecutive patients who all had a positive test for C-ANCA and PR3-ANCA between 1992 and 2002 at the Immunology laboratory at Uppsala University Hospital, Sweden. The patients' medical files were reviewed and their diagnosis re-evaluated through June 2006.

Results. 18 of the 74 ANCA-positive individuals did not present clinical evidence supportive of, or insufficient to support, a diagnosis of systemic vasculitis, but presented a range of other diseases. During a mean follow-up of 6.8 years, none of these 18 patients developed vasculitis.

Conclusions. Individuals with a positive c-ANCA and PR3-ANCA but no vasculitis at the time of testing run an unknown but likely small risk of later developing vasculitis. In this group, a positive ANCA may represent background noise (borderline titres) or be a marker of inflammatory activity rather than of vasculitic disease (high titres).

Knight, Ann

Abstract [en]

Wegener´s granulomatosis (WG) is an unusual, serious, systemic vasculitis with specific clinical findings. The studies in this thesis aim at broadening our understanding of the aetiology and outcome of WG.

Patients with WG were identified in the In-patient Register 1975-2001. During this time the incidence increased three-fold, and neither ANCA-related increased awareness, nor diagnostic drift, seem to fully explain this trend, but it is still unclear if a true rise in incidence exists.

Anti- neutrophil cytoplasmic antibodies (ANCA) have been presented as highly specific for vasculitis. In a series of consecutive cANCA/PR3-ANCA positive patients, we investigated the positive predictive value for ANCA, and the outcome of patients with a positive cANCA/PR3-ANCA but not vasculitis. These patients have a low future risk of developing vasculitis, possibly indicating that ANCA, in this setting, reflects neutrophil activating properties not specific to vasculitis.

By linkage of the WG-cohort, and randomly selected population controls, to the Multi-generation register, we identified all first-degree relatives and spouses of patients and controls, totally encompassing some 2,000 patients and 70,000 relatives. Familial aggregation of WG was the exception, with absolute risks of < 1 per 1000.However, relative risks in first-grade relatives amounted to 1.56 (95% CI 0.35-6.90) such that a moderate familial aggregation cannot be excluded.

In the WG-cohort, cancer occurrence and risk was compared to that of the general population. Patients with WG have an overall doubled risk of cancer, with particularly increased risks of bladder-cancer, haematopoietic cancers including lymphomas and squamous skin-cancer. In a case-control study nested within the WG-cohort, treatment with cyclophosphamide was compared among bladder-cancer patients and matched cancer-free controls. Absolute risk of bladder cancer as high as 10% some years after diagnosis were found, and this risk can partly be attributed to cyclophosphamide-treatment, with a dose-response relationship.